Prepubertal exposures to estradiol and some dietary estrogens, including genistein and n-3 polyunsaturated fatty acids (PUFA), have been shown to reduce carcinogen-induced mammary tumorigenesis, while an exposure during pregnancy to dietary estrogens appears to increase dams' mammary tumor incidence. It is not known whether prepubertal or pregnancy exposure to a diet composed of both genistein and n-3 PUFAs; i.e., a typical Asian diet, affects breast cancer risk. Further, the mechanisms mediating the opposing effects of prepubertal and pregnancy dietary estrogenic exposures on breast cancer risk remains to be determined. Our preliminary data suggest the prepubertal estrogen exposures up-regulate the expression of BRCA1, a tumor suppressor that participates in repairing DNA damage. High estrogenicity during pregnancy may promote the growth of premalignant cells. The goal of this study is to determine how prepubertal and pregnancy exposures to dietary estrogens mediate their effects on the breast. We will focus on BRCA1, estrogen receptor (ER) a, and cyclin D1. The three hypotheses are: HYPOTHESIS-1. Prepubertal exposure to the dietary estrogens present in soy and/or n-3 PUFA will reduce sporadic mammary tumorigenesis. HYPOTHESIS-2. Prepubertal exposure to genistein and/or n-3 PUFAs increases BRCA1 expression, which in turn alters expression of genes regulated by this tumor suppressor, including ER-a and cyclin D1. Consequently, prepubertal exposure to estrogens will increase the risk of breast cancer in BRCA1 mutant mice. HYPOTHESIS-3. An exposure during pregnancy to estrogens and dietary estrogens increases mammary tumorigenesis in dams who either have acquired mutations in tumor suppressor genes or otherwise have undergone first events of malignant transformation. The increase in risk is related to elevated ER-a expression and unopposed cellular proliferation.These hypotheses will be studied using carcinogen-initiated mammary tumors in rats, conditional BRCA1 mutant mice, and cyclin D1 transgenic mice. Further, gene microarray approach will be used to identify genes that could be regulated by altered expression of BRCA1, ER-a and cyclin D1. The results obtained in this study will be used to develop childhood and pregnancy dietary intervention strategies to prevent some breast cancers.